chr2-191031493-C-G

Position:

• chr2-191031493-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003151.4(STAT4):​c.2068G>C​(p.Asp690His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT4 NM_003151.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

Genes affected

STAT4 (HGNC:11365): (signal transducer and activator of transcription 4) The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is essential for mediating responses to IL12 in lymphocytes, and regulating the differentiation of T helper cells. Mutations in this gene may be associated with systemic lupus erythematosus and rheumatoid arthritis. Alternate splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Aug 2011]

STAT4-AS1 (HGNC:55764): (STAT4 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT4. . Gene score misZ 2.7415 (greater than the threshold 3.09). Trascript score misZ 3.1959 (greater than threshold 3.09). GenCC has associacion of gene with disabling pansclerotic morphea of childhood.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24204394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT4	NM_003151.4	c.2068G>C	p.Asp690His	missense_variant	22/24	ENST00000392320.7
STAT4-AS1	NR_136318.1	n.243+396C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT4	ENST00000392320.7	c.2068G>C	p.Asp690His	missense_variant	22/24	1	NM_003151.4	P1
STAT4-AS1	ENST00000456176.5	n.243+396C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 690 of the STAT4 protein (p.Asp690His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STAT4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1905541). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.080
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	.;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.87	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.43	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.68	P;P
Vest4		0.28
MutPred		0.23		Loss of solvent accessibility (P = 0.0117);Loss of solvent accessibility (P = 0.0117);
MVP		0.76
MPC		0.82
ClinPred		0.54	D
GERP RS		5.1
Varity_R		0.19
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs915485744; hg19: chr2-191896219;